PROJECT SUMMARY The long term goal of the Applicant's research program is to explore the molecular mechanisms underlying the etiology of age-related macular degeneration (AMD) and develop novel target-based therapeutic strategies. This K99/R00 grant will facilitate the transition for the Applicant to become an independent investigator at the Vanderbilt Eye Institute, which has a rich environment of scientific collaboration and nurturing career development of junior scientists. AMD is the leading cause of blindness in elderly Americans. The majority of AMD patients has atrophic (dry) form of the disease and has only limited treatment options at the present time. Atrophic AMD is likely resulted from gene/environmental interaction causing progressive degeneration of the retinal pigment epithelium (RPE). Aging is the most well defined environmental risk factor of AMD. We hypothesize that the mammalian target of rapamycin (mTOR)-mediated signaling pathway plays key roles in controlling the aging process of the RPE. The hypothesis is supported by recent literature data suggesting that mTOR plays key roles in integrating various environmental signals and linking them to altered tissue function and organism's life span. In our preliminary studies, we found that rapamycin reversed the senescent phenotype of primary human RPE cells in vitro. To further test our hypothesis, we have proposed three specific aims in this application. Aim 1 is to determine how the aging process regulates mTOR pathways in the RPE. Aim 2 is to determine how modulating the mTOR signaling affects RPE aging in vitro by a potential mechanism of regulating autophagy. Aim 3 is to determine whether mTOR regulates aging of the RPE in vivo using SOD1 knockout mice which develop AMD-like phenotype in the retina. During the mentored phase, the Applicant will conduct the proposed experiments under the supervision of a mentoring committee, which is consisted of mentors with expertise in AMD etiology and pathogenesis (Dr. Paul Sternberg), animal models of neurodegeneration in the retina (Dr. David Calkins) and mTOR/autophagy (Dr. Lu Bo). Members of the committee will meet regularly, monitor the research progress and assist the Applicant to advance her career towards independence. Research at the R00 phase will test the potential therapeutic effects of mTOR inhibitors in an animal model relevant to AMD. Results from these studies will provide novel mechanistic information on aging and age-related degeneration of the RPE and retina.